The goal of this application is to investigate the safety, efficacy, and mechanisms of action of American ginseng (AG) in the treatment of HIV-related fatigue, a widespread symptom in patients with HIV/AIDS that is associated with functional and psychological morbidity and poor quality of life. The mechanisms of HIV-related fatigue are not well understood;however, a role for increased concentrations of pro-inflammatory cytokines has been proposed. Few pharmacologic interventions are available to decrease fatigue in HIV-infected patients, and clinical trials of most have been limited. Preliminary data in cancer patients suggest that AG can improve fatigue. Thus, AG could also have therapeutic benefits for patients coping with HIV-related fatigue. AG is already widely used by patients with HIV/AIDS, alone or in combination with antiretroviral (ARV) drugs. However, despite its widespread use, the safety and efficacy of AG in treating HIV-related fatigue have not been formally evaluated. In particular, the herb-drug interactions between AG and ARV drugs have not been fully investigated. Herb-ARV interactions primarily involve the modulation of ARV-metabolizing cytochrome P450 (CYP450) isoenzymes, which in turn can alter drug efficacy and/or toxicity. Preliminary data indicate that AG does not significantly affect CYP3A4 activity, the major metabolic pathway for most ARV drugs. However, data are lacking for CYP2B6, another important isoenzyme. The following specific aims will test the hypothesis that a standardized AG formulation can improve HIV-related fatigue without causing significant herb-drug interactions: Aim 1. To determine the steady-state plasma concentrations of the CYP2B6 substrate, efavirenz, in healthy volunteers, before and after 14 days of concurrent treatment with AG. Aim 2. To determine the impact of AG on fatigue in HIV-infected patients in a randomized, placebo-controlled, dose-escalating (1000, 2000, and 3000 mg/day) clinical trial over 6 weeks. Pro-inflammatory cytokines will also be quantified in order to elucidate the mechanism of HIV-related fatigue and the effects of AG on these markers. This application will allow the applicants to rigorously investigate a novel treatment for HIV-related fatigue and expand the current knowledge of herbal-ARV interactions. PUBLIC HEALTH RELEVANCE: Fatigue is a debilitating symptom in HIV-infection. The etiology of fatigue in HIV-infected patients is unknown, but possible underlying mechanisms may include changes in systemic inflammation. Our goal is to determine the safety, efficacy, and mechanisms of action of American ginseng for treatment of fatigue in HIV infection.